Recent work from this and other laboratories supports the concept that serious injury drives the innate immune and adaptive immune systems in opposite directions. The innate immune system displays an increased pro-inflammatory phenotype, while cells of the adaptive immune system show a concomitant shift to a dominant counter-inflammatory phenotype. This imbalance in immune responses can predispose the seriously injured host to developing opportunistic infections and can result in excessive, life-threatening inflammatory reactivity against pathogens. We have recently reported that injury causes a significant upregulation of regulatory CD4 T cell (Treg) activity and that Tregs play an active role in controlling the development of enhanced innate immune system reactivity after injury. The central purpose of this project is to investigate the factors that influence Treg activity after injury and to provide a more thorough understanding of the role of Tregs in controlling the innate and adaptive immune response. The specific aims will address the hypothesis that injury induces a Treg response that contributes to the development of post- injury immune suppression and that Tregs control the proinflammatory phenotype displayed by the innate immune system following injury. The project will use a well-established mouse model to study mechanisms responsible for changes in Tregs after injury and will include translational studies to identify changes in human Treg phenotype in critically-injured patients. The specific aims of this project are: 1) To identify the pathways responsible for increased regulatory activity of Treg cells after injury. 2) To define the contribution of Tregs to host defenses and immune response regulation following injury. And 3) to determine the significance of Tregs in controlling the innate immune system reactivity after injury. The studies will use mice made deficient in Treg cells along with mice lacking CD4 T-cells to address the interplay between injury and the activation of Treg cells or conventional CD4 T-cells. Assays for measuring human Treg phenotype and function have been developed in our laboratory and will be used to determine if phenotypic changes in Tregs contributes to the development of post-injury complications. Relevance of this project to public health: The results of this research will advance our current understanding of how major injury alters immune system regulation. An improved understanding of the injury response will provide insight into the development of specific immune system enhancing or controlling drugs that could protect critically injured patients from developing secondary infections and complications that can occur after major trauma.